National Institute for Biotechnology in the Negev, Ben Gurion University, Beer-Sheva, Israel.
Am J Hum Genet. 2010 Nov 12;87(5):713-20. doi: 10.1016/j.ajhg.2010.10.008. Epub 2010 Oct 28.
Excessive chloride secretion in sweat (hyperchlorhidrosis), leading to a positive sweat test, is most commonly indicative of cystic fibrosis yet is found also in conjunction with various metabolic, endocrine, and dermatological disorders. There is conflicting evidence regarding the existence of autosomal-recessive hyperchlorhidrosis. We now describe a consanguineous Israeli Bedouin kindred with autosomal-recessive hyperchlohidrosis whose sole symptoms are visible salt precipitates after sweating, a preponderance to hyponatremic dehydration, and poor feeding and slow weight gain at infancy. Through genome-wide linkage analysis, we demonstrate that the phenotype is due to a homozygous mutation in CA12, encoding carbonic anhydrase XII. The mutant (c.427G>A [p.Glu143Lys]) protein showed 71% activity of the wild-type enzyme for catalyzing the CO₂ hydration to bicarbonate and H(+), and it bound the clinically used sulfonamide inhibitor acetazolamide with high affinity (K(I) of 10 nM). Unlike the wild-type enzyme, which is not inhibited by chloride, bromide, or iodide (K(I)s of 73-215 mM), the mutant is inhibited in the submicromolar range by these anions (K(I)s of 0.37-0.73 mM).
汗液中氯离子分泌过多（多汗症），导致汗液试验阳性，这最常见于囊性纤维化，但也与各种代谢、内分泌和皮肤病有关。关于常染色体隐性多汗症是否存在存在争议。我们现在描述了一个有血缘关系的以色列贝都因家族，他们患有常染色体隐性多汗症，其唯一的症状是出汗后可见盐沉淀，易发生低钠血症脱水，婴儿期喂养不良且体重增长缓慢。通过全基因组连锁分析，我们证明该表型是由于 CA12 基因的纯合突变所致，该基因编码碳酸酐酶 XII。突变型（c.427G>A [p.Glu143Lys]）蛋白对 CO₂水合作用生成碳酸氢盐和 H(+)的催化活性为野生型酶的 71%，并且它与临床上使用的磺胺类抑制剂乙酰唑胺具有高亲和力（K(I)为 10 nM）。与野生型酶不同，氯离子、溴离子或碘离子（K(I)s 为 73-215 mM）不会抑制其活性，而这种突变型在亚微摩尔范围内被这些阴离子抑制（K(I)s 为 0.37-0.73 mM）。
